Synthesis of non-symmetric N-benzylbispidinol amides and study of their inhibitory activity against the main protease of the SARS-CoV-2 virus

A I Dalinger; D S Baev; O I Yarovaya; V Yu Chirkova; E A Sharlaeva; S V Belenkaya; D N Shcherbakov; N F Salakhutdinov; S Z Vatsadze

doi:10.1007/s11172-023-3729-x

Synthesis of non-symmetric N-benzylbispidinol amides and study of their inhibitory activity against the main protease of the SARS-CoV-2 virus

Russ Chem Bull. 2023;72(1):239-247. doi: 10.1007/s11172-023-3729-x. Epub 2023 Feb 14.

Authors

A I Dalinger¹, D S Baev², O I Yarovaya², V Yu Chirkova³, E A Sharlaeva³, S V Belenkaya^{4

5}, D N Shcherbakov^{3

5}, N F Salakhutdinov², S Z Vatsadze⁶

Affiliations

¹ Lomonosov Moscow State University, Build. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation.
² N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 prosp. Acad. Lavrentieva, 630090 Novosibirsk, Russian Federation.
³ Altai State University, 61 prosp. Lenina, 656049 Barnaul, Russian Federation.
⁴ Novosibirsk State University, 2 ul. Pirogova, 630090 Novosibirsk, Russian Federation.
⁵ Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, State Research Center of Virology and Biotechnology VECTOR, 630559 Koltsovo, Novosibirsk region, Russian Federation.
⁶ N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991 Moscow, Russian Federation.

Abstract

Based on the data obtained by molecular modeling of the non-covalent interaction of non-symmetric N-benzylbispidin-9-ol amides with the active site of the main protease 3CLpro of the SARS-CoV-2 virus, a series of compounds was synthesized, and their inhibitory activity against 3CLpro was studied and compared with that of the known inhibitor ML188 (IC₅₀ = 1.56±0.55 µmol L^-1). It was found that only compound 1g containing the 1,4-dihydroindeno[1,2-c]pyrazole fragment showed moderate activity (IC₅₀ = 100±5.7µmol L^-1) and was characterized by the highest calculated binding energy among the studied bispidine derivatives according to molecular docking data.

Keywords: 3CLpro; SARS-CoV-2; amides; bispidine; inhibition; main viral protease; molecular docking.